Episodic positive selection accumulates through time in seasonal influenza A, with no climatic signature

Abstract

The haemagglutinin (HA) and neuraminidase (NA) genes of seasonal influenza A evolve under continual immune-driven positive selection. To test whether the tempo of selection has changed over time, we mapped branch- and site-specific episodic diversifying selection (MEME) onto Bayesian relaxed-clock time trees for HA and NA in H1N1 and H3N2, across multiple countries and four sequence-subsampling schemes. We dated each selection episode and tested whether episodes accumulated through time after accounting for the growing number of sampled lineages. Positive-selection episodes increased over time in every gene-subtype combination, at about 2-6% per lineage-year, and rose faster for NA than HA. Episodes were concentrated at a small number of codon sites, especially recurrent sites in H3N2 HA that fell within canonical antigenic regions of the HA1 head. This increase was robust to subsampling scheme and time-bin width, and was driven disproportionately by recent lineages. A detrended spatial analysis found no association with latitude or temperature anomalies. Overall, positive selection on influenza surface antigens appears to be intensifying through time, most likely because of immune escape and expanded surveillance rather than climate warming.